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The complexity of NF-κB signaling in inflammation and cancer.

Hoesel B, Schmid JA - Mol. Cancer (2013)

Bottom Line: The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.

ABSTRACT
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.

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Related in: MedlinePlus

Members of the NF-κB signaling pathway and the IκB kinase-complex. (A) The five members of the NF-κB family of proteins: RelA (p65), RelB, c-Rel,NF-κB1 (p105), and NF-κB2 (p100). p105 and p100 are processed to their shorter forms p50 and p52, respectively. All members of the NF-κB family harbor an N-terminal Rel homology domain (RHD), which mediates DNA contact and homo- and heterodimerization. Three family members (RelA, RelB and c-Rel) contain C-terminal transactivation domains (TAs), which are essential for transcriptional activity. (B) The IκB family of proteins consists of four members: IκBα, IκBβ, IκBϵ and BCL-3. These proteins are characterized by the presence of ankyrin (ANK) repeats, which mediate binding of IκBs to the NF-κB family of proteins. Based on the presence of ankyrin repeats, p100 and p105 can also be included into the IκB family – as their DNA-binding RHD domain is covalently linked to an IκB-like inhibitory domain. In addition to the ANK repeats IκBα and IκBβ contain PEST domains, which are enriched in proline, glutamate, serine and threonine and are required for constitutive turnover. BCL-3 differs from other IκB family members by containing TA domains, which mediate transcriptional activity when BCL-3 is associated with NF-κB dimers that bind to DNA. (C) The three most important members of IκB kinase (IKK) complex: NF-κB Essential Modulator (NEMO or IKKγ), IκB kinase α, (IKKα or IKK1) and IκB kinase β (IKKβ or IKK2). Further abbreviations: leucin-zipper-like motif (LZ), death domain (DD), coiled-coil domain (CC), zinc-finger domain (ZF), helix-loop-helix domain (HLH), NEMO-binding domain (NBD). It is important to note that the total number of amino acids of protein as well as the start and end of some domains can differ between publications and databases.
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Figure 1: Members of the NF-κB signaling pathway and the IκB kinase-complex. (A) The five members of the NF-κB family of proteins: RelA (p65), RelB, c-Rel,NF-κB1 (p105), and NF-κB2 (p100). p105 and p100 are processed to their shorter forms p50 and p52, respectively. All members of the NF-κB family harbor an N-terminal Rel homology domain (RHD), which mediates DNA contact and homo- and heterodimerization. Three family members (RelA, RelB and c-Rel) contain C-terminal transactivation domains (TAs), which are essential for transcriptional activity. (B) The IκB family of proteins consists of four members: IκBα, IκBβ, IκBϵ and BCL-3. These proteins are characterized by the presence of ankyrin (ANK) repeats, which mediate binding of IκBs to the NF-κB family of proteins. Based on the presence of ankyrin repeats, p100 and p105 can also be included into the IκB family – as their DNA-binding RHD domain is covalently linked to an IκB-like inhibitory domain. In addition to the ANK repeats IκBα and IκBβ contain PEST domains, which are enriched in proline, glutamate, serine and threonine and are required for constitutive turnover. BCL-3 differs from other IκB family members by containing TA domains, which mediate transcriptional activity when BCL-3 is associated with NF-κB dimers that bind to DNA. (C) The three most important members of IκB kinase (IKK) complex: NF-κB Essential Modulator (NEMO or IKKγ), IκB kinase α, (IKKα or IKK1) and IκB kinase β (IKKβ or IKK2). Further abbreviations: leucin-zipper-like motif (LZ), death domain (DD), coiled-coil domain (CC), zinc-finger domain (ZF), helix-loop-helix domain (HLH), NEMO-binding domain (NBD). It is important to note that the total number of amino acids of protein as well as the start and end of some domains can differ between publications and databases.

Mentions: The transcription factor NF-κB was discovered in 1986 as a nuclear factor that binds to the enhancer element of the immunoglobulin kappa light-chain of activated B cells (thereby coining the abbreviation NF-κB) [1]. Soon afterwards it became clear that proteins, which harbor this specific DNA binding activity are expressed in nearly all cell types and regulate many target genes with a whole variety of functions [2]. In total, five members of this transcription factor family have been identified, designated as p65 (RelA), RelB, c-Rel, NF-κB1 and NF-κB2 (Figure 1A). In contrast to the other family members, NF-κB1 and NF-κB2 are synthesized as pro-forms (p105 and p100) and are proteolytically processed to p50 and p52 (Figure 1A, black arrows), respectively [3]. All five members of this protein family form homo- or heterodimers and share some structural features, including a Rel homology domain (RHD), which is essential for dimerization as well as binding to cognate DNA elements [4]. In most quiescent cells these dimers are bound to inhibitory molecules of the IκB family of proteins (inhibitors of NF-κB) (Figure 1B). These inhibitors are characterized by ankyrin repeats, which associate with the DNA-binding domains of the transcription factors thereby making them transcriptionally inactive. Interestingly, p105 and p100, the precursors of p50 and p52, also contain ankyrin repeats, which are cleaved upon maturation - thus comprising their own internal inhibitors. In contrast to the other members of the NF-κB family these two proteins do not contain a transactivation domain [5]. As a consequence, dimers of p50 and p52, which bind to NF-κB elements of gene promoters, act as transcriptional repressors [6]. However, when p50 or p52 are bound to a member containing a transactivation domain, such as p65 or RelB, they constitute a transcriptional activator. Another interesting aspect is that one member of the IκB family, Bcl-3, also contains transactivation domains (Figure 1B) and can bind to dimers of p50 and p52 rendering the complex transcriptionally active [7-9]. The complexity of this transcriptional regulation system is also augmented by the fact that different NF-κB dimers have differential preferences for variations of the DNA-binding sequence [10]. Thus different target genes are differentially induced by distinct NF-κB dimers. Furthermore, NF-κB subunits also contain sites for phosphorylations and other post-translational modifications which are important for activation and crosstalk with other signaling pathways [11]. Binding of NF-κB dimers to IκB molecules does not only prevent binding to DNA, but also shifts the steady-state localization of the complex to the cytosol. Nevertheless, shuttling between cytosol and nucleus does occur [12,13], which might be a basis for a low basal transcriptional activity of NF-κB given that the IκB/NF-κB complex is subject to dissociation and re-association processes.


The complexity of NF-κB signaling in inflammation and cancer.

Hoesel B, Schmid JA - Mol. Cancer (2013)

Members of the NF-κB signaling pathway and the IκB kinase-complex. (A) The five members of the NF-κB family of proteins: RelA (p65), RelB, c-Rel,NF-κB1 (p105), and NF-κB2 (p100). p105 and p100 are processed to their shorter forms p50 and p52, respectively. All members of the NF-κB family harbor an N-terminal Rel homology domain (RHD), which mediates DNA contact and homo- and heterodimerization. Three family members (RelA, RelB and c-Rel) contain C-terminal transactivation domains (TAs), which are essential for transcriptional activity. (B) The IκB family of proteins consists of four members: IκBα, IκBβ, IκBϵ and BCL-3. These proteins are characterized by the presence of ankyrin (ANK) repeats, which mediate binding of IκBs to the NF-κB family of proteins. Based on the presence of ankyrin repeats, p100 and p105 can also be included into the IκB family – as their DNA-binding RHD domain is covalently linked to an IκB-like inhibitory domain. In addition to the ANK repeats IκBα and IκBβ contain PEST domains, which are enriched in proline, glutamate, serine and threonine and are required for constitutive turnover. BCL-3 differs from other IκB family members by containing TA domains, which mediate transcriptional activity when BCL-3 is associated with NF-κB dimers that bind to DNA. (C) The three most important members of IκB kinase (IKK) complex: NF-κB Essential Modulator (NEMO or IKKγ), IκB kinase α, (IKKα or IKK1) and IκB kinase β (IKKβ or IKK2). Further abbreviations: leucin-zipper-like motif (LZ), death domain (DD), coiled-coil domain (CC), zinc-finger domain (ZF), helix-loop-helix domain (HLH), NEMO-binding domain (NBD). It is important to note that the total number of amino acids of protein as well as the start and end of some domains can differ between publications and databases.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3750319&req=5

Figure 1: Members of the NF-κB signaling pathway and the IκB kinase-complex. (A) The five members of the NF-κB family of proteins: RelA (p65), RelB, c-Rel,NF-κB1 (p105), and NF-κB2 (p100). p105 and p100 are processed to their shorter forms p50 and p52, respectively. All members of the NF-κB family harbor an N-terminal Rel homology domain (RHD), which mediates DNA contact and homo- and heterodimerization. Three family members (RelA, RelB and c-Rel) contain C-terminal transactivation domains (TAs), which are essential for transcriptional activity. (B) The IκB family of proteins consists of four members: IκBα, IκBβ, IκBϵ and BCL-3. These proteins are characterized by the presence of ankyrin (ANK) repeats, which mediate binding of IκBs to the NF-κB family of proteins. Based on the presence of ankyrin repeats, p100 and p105 can also be included into the IκB family – as their DNA-binding RHD domain is covalently linked to an IκB-like inhibitory domain. In addition to the ANK repeats IκBα and IκBβ contain PEST domains, which are enriched in proline, glutamate, serine and threonine and are required for constitutive turnover. BCL-3 differs from other IκB family members by containing TA domains, which mediate transcriptional activity when BCL-3 is associated with NF-κB dimers that bind to DNA. (C) The three most important members of IκB kinase (IKK) complex: NF-κB Essential Modulator (NEMO or IKKγ), IκB kinase α, (IKKα or IKK1) and IκB kinase β (IKKβ or IKK2). Further abbreviations: leucin-zipper-like motif (LZ), death domain (DD), coiled-coil domain (CC), zinc-finger domain (ZF), helix-loop-helix domain (HLH), NEMO-binding domain (NBD). It is important to note that the total number of amino acids of protein as well as the start and end of some domains can differ between publications and databases.
Mentions: The transcription factor NF-κB was discovered in 1986 as a nuclear factor that binds to the enhancer element of the immunoglobulin kappa light-chain of activated B cells (thereby coining the abbreviation NF-κB) [1]. Soon afterwards it became clear that proteins, which harbor this specific DNA binding activity are expressed in nearly all cell types and regulate many target genes with a whole variety of functions [2]. In total, five members of this transcription factor family have been identified, designated as p65 (RelA), RelB, c-Rel, NF-κB1 and NF-κB2 (Figure 1A). In contrast to the other family members, NF-κB1 and NF-κB2 are synthesized as pro-forms (p105 and p100) and are proteolytically processed to p50 and p52 (Figure 1A, black arrows), respectively [3]. All five members of this protein family form homo- or heterodimers and share some structural features, including a Rel homology domain (RHD), which is essential for dimerization as well as binding to cognate DNA elements [4]. In most quiescent cells these dimers are bound to inhibitory molecules of the IκB family of proteins (inhibitors of NF-κB) (Figure 1B). These inhibitors are characterized by ankyrin repeats, which associate with the DNA-binding domains of the transcription factors thereby making them transcriptionally inactive. Interestingly, p105 and p100, the precursors of p50 and p52, also contain ankyrin repeats, which are cleaved upon maturation - thus comprising their own internal inhibitors. In contrast to the other members of the NF-κB family these two proteins do not contain a transactivation domain [5]. As a consequence, dimers of p50 and p52, which bind to NF-κB elements of gene promoters, act as transcriptional repressors [6]. However, when p50 or p52 are bound to a member containing a transactivation domain, such as p65 or RelB, they constitute a transcriptional activator. Another interesting aspect is that one member of the IκB family, Bcl-3, also contains transactivation domains (Figure 1B) and can bind to dimers of p50 and p52 rendering the complex transcriptionally active [7-9]. The complexity of this transcriptional regulation system is also augmented by the fact that different NF-κB dimers have differential preferences for variations of the DNA-binding sequence [10]. Thus different target genes are differentially induced by distinct NF-κB dimers. Furthermore, NF-κB subunits also contain sites for phosphorylations and other post-translational modifications which are important for activation and crosstalk with other signaling pathways [11]. Binding of NF-κB dimers to IκB molecules does not only prevent binding to DNA, but also shifts the steady-state localization of the complex to the cytosol. Nevertheless, shuttling between cytosol and nucleus does occur [12,13], which might be a basis for a low basal transcriptional activity of NF-κB given that the IκB/NF-κB complex is subject to dissociation and re-association processes.

Bottom Line: The NF-κB family of transcription factors has an essential role in inflammation and innate immunity.During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways.Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.

ABSTRACT
The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.

Show MeSH
Related in: MedlinePlus